1.alpha.,25-(OH).sub.2 --V.D.sub.3 (1.alpha.,25-dihydroxylcholecalciferol), 1.alpha.,24-(OH).sub.2 --V.D.sub.3 (1.alpha.,24-dihydroxylcholecalciferol), etc. exhibit a Ca-homeostasis regulating action, which is known as a biological action of V.D.sub.3, and therefore, are called active-type V.D.sub.3 s. The biological actions of active type V.D.sub.3 s are diverse. In addition to the above-mentioned Ca-homeostasis regulating action, mention may be made of an action of bone formation, an action of inducing cell differentiation, an action of suppressing the secretion of the para-thyroid hormone, etc. Among these, regarding the Ca-homeostasis regulating action, the above substances are already being clinically administered as oral formulations for treatment of osteoporosis, osteomalacia, and other so-called osteopenia and are recognized to have superior therapeutic effect. On the other hand, clinical application has been studied for the action in inducing cell differentiation, though later than with the Ca-homeostasis regulating action. In particular, since the hard-to-cure skin disease of psoriasis is considered to be caused by the incomplete undifferentiation and accelerated proliferation of epidermic cells, application of active-type V.D.sub.3 s has been studied. As psoriasis is a disease of the epidermis, the outer layer of the skin, local administration to the affected location of the skin is more advantageous over oral administration, injection, and other general administration in terms of bioavailability and also enables prevention of general side effects, and is therefore considered as a best method of administration.
Dosage forms for local skin administration include ointments, creams, and other semisolid agents, tape agents, cataplasms, powder agents, etc., but when considering the symptoms of psoriasis, semisolid agents are best. As a 1.alpha.,24-(OH).sub.2 --V.D.sub.3 ointment, the present inventors have already disclosed a formula for an water-free ointment (see the specification of Japanese Examined Patent Publication (Kokoku) No. 3-68009). Good therapeutic effects have been reported by this water-free ointment, but since the base of the ointment is white petrolatum, it is not possible to avoid an oily, sticky feeling after application. Therefore, there has been a need for an external formulations improved in the feeling when applied onto the face etc.
Cream compositions include large amounts of water, and therefore, are not sticky as with ointments and have been used for a long time as external agents. They are classified by composition into two types of emulsion type cream compositions, that is, oil-in-water types (O/W) or water-in-oil types (W/O), as well as aqueous gel type cream compositions. A comparison of these three types by the state when rubbed on the skin shows that the aqueous gel type cream compositions suffer from the problem of the gel base polymer precipitating on the skin, while the water-in-oil type (W/O) emulsion cream compositions suffer from the problem that the white color and other external colors do not easily vanish. As opposed to this, oil-in-water type (O/W) emulsion cream compositions are advantageous in that the white color and other external colors easily vanish.
However, in the case of psoriasis, in particular, since it occurs mostly on the face, an oil-in-water type emulsion cream composition has been desired which not only enables the external color to vanish, but also which does not stand out at the applied location, in particular does not shine at the applied location, and therefore, feels good upon application.
Oil-in-water type emulsion cream compositions are composed of an oil phase consisting of a solid oil component which is normally mainly solid or semisolid at ordinary temperature and a liquid oil component which is liquid at ordinary temperature, an aqueous phase including propylene glycol or glycerine or another humectant etc., a surfactant, etc. (For general technology regarding these cream compositions, see for example "Shin Keshohingaku" (New Cosmetic Science), edited by Takeo Mitsui, 1993, Nanzando.)
As the above-mentioned solid oil component, normally use is made of white petrolatum, solid paraffin, and other hydrocarbons; cetyl alcohol, stearyl alcohol, and other higher alcohols; palmitic acid and other higher fatty acids; beeswax, carnauba wax, and other waxes (esters); and lanolin and other sterol esters and as the above-mentioned liquid oil component, liquid paraffin, squalane, and other hydrocarbons; medium chain-length fatty acid triglyceride, almond oil, olive oil, diisopropyl adipate, and other esters etc. (Dermatological Formulation: B. W. Barry, Marcel Dekker Co., 1983).
Further, as the above-mentioned surfactant, many nonionic surfactants and ionic surfactants are used alone or in combinations with two types or more. For emulsification of an oil-in-water type emulsion, the HLB value of the surfactant is, in general, said to be suitably in the range of approximately 8 to approximately 18. (For example, see "Bunsan Nyukakei no Kagaku" (Chemistry of Dispersions and Emulsions), Kitahara et al, 1988 Kogaku Tosho, p. 63.)
Several prior arts have already been disclosed for cream compositions of active-type V.D.sub.3 s.
For example, the specification of EP-A-0,129,003 discloses a cream composition of 1.alpha.-OH--V.D.sub.3 or 1.alpha.,25-(OH).sub.2 --V.D.sub.3 and describes a cream composition formula of 20 parts by weight of beeswax as the solid oil component and 40 parts by weight of liquid paraffin and 1 part by weight of almond oil as the liquid oil component. Further, the specification of Japanese Unexamined Patent Publication (Kokai) No. 60-174705 discloses a cream composition of 1.alpha.,25-(OH).sub.2 --V.D.sub.3 and describes a cream composition formula including a solid oil component comprising petrolatum, beeswax, higher fatty acids, etc. and a liquid oil component comprising liquid paraffin, squalane, etc.
Further, the specification of Japanese Unexamined Patent Publication (Kokai) No. 4-210903 discloses an emulsion-type local administered medicinal composition of 1.alpha.,25-(OH).sub.2 --V.D.sub.3, describes a cream composition formula including cetyl alcohol, stearyl alcohol, and other solid oil components (NOTE: the specification describes them as viscosity adjusters) and liquid paraffin and other liquid oil components (NOTE: the specification describes them as lyophilic solubilizers) etc., and states that the chemical stability of the 1.alpha.,25-(OH).sub.2 --V.D.sub.3 in the 1.alpha.,25-(OH).sub.2 --V.D.sub.3 emulsion composition is achieved by adjusting the pH to approximately 6.5 to approximately 7.5.
Further, the specification of WO92/01454 and the specification of WO91/1280 disclose cream compositions of recalcipotriol or a 20(R)-22-oxa-V.D.sub.3 derivative and describes a cream composition formula including a solid oil component comprising white petrolatum, stearyl alcohol, and the like and a liquid oil component comprising liquid paraffin.
These illustrated cream compositions or emulsion compositions are comprised of components used for normal cream composition preparations. (For example, see the above-mentioned book of Barry.) As a feature of the components or proportions deserving special mention, it was stated in the specification of Japanese Unexamined Patent Publication (Kokai) No. 4-210903 that the pH should be controlled to approximately 6.5 to approximately 7.5 for stabilization of the active ingredient, but nothing further was touched upon. That is, nothing particular was observed regarding the components making up the oil phase or the components of the surfactant.
The present inventors, however, engaged in intensive studies of various types of cream compositions prepared in accordance with the technology disclosed above with the intention of producing a cream composition of 1.alpha.,24-(OH).sub.2--V.D.sub.3, which is one of active-type V.D.sub.3, and as a result, ran into the problems that (1) in the prior art, it was not possible to obtain sufficient skin permeability of the active ingredient 1.alpha.,24-(OH).sub.2 --V.D.sub.3 or to achieve a superior pharmacological effect in animal tests (in particular, these were worse than the ointment of the present inventors (see specification of Japanese Examined Patent Publication (Kokoku) No. 3-68009), (2) in the prior art, there was room for improvement of the chemical stability of the active ingredient 1.alpha.,24-(OH).sub.2 --V.D.sub.3, (3) some of the cream compositions made by the previously disclosed technology were found to be insufficient in terms of physical stability, and (4) some of the cream compositions made by the previously disclosed technology were found to be insufficient in terms of the feeling, such as stickiness upon application to the skin or shininess of the applied location.
Namely, in the 1.alpha.,24-(OH).sub.2 --V.D.sub.3 cream compositions made using 1.alpha.,24-(OH).sub.2 --V.D.sub.3 as the active ingredient in accordance with formulas disclosed in the specification of EP-A-0,129,003, the specification of Japanese Unexamined Patent Publication (Kokai) No. 60-174705, the specification of Japanese Unexamined Patent Publication (Kokai) No. 4-210903, and the specifications of WO92/01454 and WO91/1280, both the skin permeability and the pharmacological effect of the 1.alpha.,24-(OH).sub.2 --V.D.sub.3 were inferior to the ointment of the present inventors (see specification of Japanese Examined Patent Publication (Kokoku) No. 3-68009) and there was room for improvement in the chemical stability as well.
Further, the formulas disclosed in the specification of EP-A-0,129,003 and the specification of Japanese Unexamined Patent Publication (Kokai) No. 60-174705 suffered from the problems of stickiness at the time of coating, shininess of the applied location, and physical stability, i.e., easy separation of the oil phase and water phase under heating or under contrifugation. Further, in the formula disclosed in the specification of Japanese Unexamined Patent Publication (Kokai) No. 4-210903, there was the problem of physical stability, i.e., the easy separation of the oil phase and aqueous phase under heating or contrifugation. In the formula illustrated in WO92/01454 and 91/1280, shininess of the applied location could not be eliminated.
That is, while these disclosed prior art did give several examples of formulas of active-type V.D.sub.3 emulsion compositions (e.g., cream compositions), the skin permeability and pharmacological activity and the chemical stability of the 1.alpha.,24-(OH).sub.2 --V.D.sub.3 were insufficient and the physical stability of the cream composition and the feeling upon application were not necessarily satisfactory either.